Abstract This mechanistic, proof of concept study tests the hypothesis that augmentation of suppressed N-Methyl-D-aspartate Receptor (NMDAR) function following pediatric moderate/severe traumatic brain injury (TBI) with D-cycloserine (DCS) will increase neural activation, and when used in conjunction with cognitive training will enhance the effect of cognitive training on working memory (WM). Study participants will be children who completed our currently funded study of neurocognitive recovery during the first year post-TBI. In this double blind, parallel, placebo controlled study children with moderate and severe TBI will be randomized to one of two treatment arms. Both treatment arms will receive six weeks of cognitive training from a computer training program shown in prior studies to improve WM. Participants will receive DCS or a placebo in addition to cognitive training. At baseline participants in both treatment arms will undergo fMRI before and after administration of the first dose of drug to test the hypothesis that DCS increases neural activation. This pharmacological MRI paradigm may be a biomarker for the mechanism for the therapeutic effects of DCS on cognitive function. In the baseline evaluation neuropsychological tests of WM and executive functioning and parent's ratings of their child's WM and executive functioning will be administered to provide a basis for assessing generalization. After six weeks of training, the same battery of evaluations will be readministered, with the exception on only one fMRI evaluation, to determine whether children treated with DCS improved more on the trained WM tests and showed greater generalization than children receiving placebo. After treatment has been terminated for three months the children will complete one session of cognitive training and will be retested on the non-trained measures of WM and EF and their parents will complete questionnaires to assess the maintenance of training. This study will collect preliminary data to support attempts to identify a new target (NMDAR mediated neural plasticity) for developing drugs that enhance neurocognitive recovery and a biomarker (pharmocological fMRI) for that target.